Distinct IL‑17A and retinoic acid–associated gene programs are enriched in epithelialized tunnels in severe hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease in which severe disease is characterized by epithelialized dermal tunnels that are poorly responsive to medical therapy. We used spatial transcriptomics to show that severe HS tunnel epithelium have a conserved transcriptional program different from that of the overlying epidermis. Pathway and differential gene intersection analyses demonstrated that IL-17A signaling is the dominant cytokine-associated driver of tunnel inflammation, whereas TNFa signaling showed minimal overlap with the tunnel signature. Unexpectedly, transcription factor enrichment and gene set enrichment analyses identified dysregulated retinoic acid (RA)-associated signaling in tunnels. Functional studies in primary keratinocytes revealed that IL-17A upregulated a subset of RA-associated tunnel genes through a mechanism independent of retinoic acid receptor (RAR) signaling. Another distinct subset of tunnel-associated genes, including mucosal keratins such as KRT13, was not induced by IL-17A but instead required RAR signaling for their expression. Together, these findings define HS tunnels as a spatially distinct epithelial state shaped by IL 17A–associated inflammation and altered retinoid signaling, highlighting potential targets for tunnel directed intervention in HS.